Dopamine is a catecholamine which is one of the principal neurotransmitters present in the central nervous system. Abnormalities in dopaminergic neurotransmission have been implicated in a variety of disease states including Parkinson's disease, depression, attention deficit disorder, and drug addiction.
The major pathway by which monoamines are inactivated is by being transported back into the cell that released them via specific transporter proteins (i.e. serotonin, norepinephrine, and dopamine transporter proteins). The dopamine transporter protein is the carrier molecule which transports dopamine across the synaptic membrane (Hitri et al., Clinical Neuropharmacology, 1994, 17, 1-22). The human dopamine transporter protein was recently cloned, and shown to have several binding sites, including a binding site for cocaine (Giros et al., Mol. Pharmacol., 1992, 42, 383-390).
Major depression, which is characterized by feelings of intense sadness or pessimistic worry, affects approximately 5-10% of the population (Michels, (ed.) Psychiatry Philadelphia: Lipincott, 1992). A variety of medications have shown efficacy in treating depression including the tricyclic antidepressants, serotonin uptake inhibitors, and monoamine oxidase inhibitors (Pinder et al., Med. Res. Rev., 1993, 13, 259-325). All of these compounds work by increasing the synaptic levels of monoamine neurotransmitters. There are several reports in the literature of selective dopamine uptake inhibitors showing efficacy in animal models of depression (Nielsen et al., Adv. Biosci., 1990, 77, 101-108; Randrup et al., Psychopharmacology, 1977, 52, 73-77; Halaris et al., Biochem. Pharmacol., 1975, 24, 1896-1897).
Parkinson's disease is a progressive, degenerative neurologic motor disorder produced by the loss of dopaminergic neurons in the substantia nigra. This in turn results in abnormally low levels of dopamine present in the striatum. As a result, drugs that can increase the levels of dopamine have the potential to be useful in the treatment of Parkinson's Disease. The most widely prescribed drug in this class is the dopamine precursor levodopa (L-DOPA) (McDowell et al., Ann. Intern. Med., 1970, 72, 29-35). Another mechanism to increase levels of synaptic dopamine is to block its reuptake via inhibition of the dopamine transporter protein. There have been several studies demonstrating that compounds which act by inhibiting the action of the dopamine transporter protein are effective in animal models of Parkinson's Disease (Mayer et al., MPTP: Neurotoxin Prod. Parkinsonian Syndr., Markey et al., ed., 1985, 585-589). For example, the selective dopamine uptake inhibitor GBR 13,098 is effective at preventing MPTP induced toxicity in mice (Pileblad et al., Neuropharmacology, 1985, 24, 689-692).
Attention deficit disorder (ADD) manifests itself primarily in children. The symptoms include an inability to remain focused on a particular task for an extended period of time (Funk et al., Pediatrics, 1993, 91, 816-819). A variety of drugs have been prescribed for this disease, including dextroamphetamine and methylphenidate. Methylphenidate appears to exert its effects by inhibiting the dopamine transporter, more specifically by binding to the cocaine site on the dopamine transporter (Volkow et al., Arch. Gen. Psychiatry, 1995, 52, 456-63). As a result, compounds which have a similar mode of action at this binding site may also show efficacy in this disease.
Cocaine addiction affects approximately 2.1 million people in the United States (Committee to Study Medication Development and Research at the National Institute on Drug Abuse, "Extent of Illicit Drug Use", Development of Medications for the Treatment of Opiate and Cocaine Additions: Issues for the Government and Private Sector, Fulco, Liverman, Earley, Eds., National Academy Press, Washington, D.C., 1995, 36-37). In the last decade the molecular site of cocaine's addictive properties has been determined to be the dopamine transporter protein (Kuhar et al., TIPS, 1991, 14, 299-302). It was originally proposed that cocaine was a competitive inhibitor of dopamine uptake, coincident with cocaine and dopamine having common binding domains on the transporter protein. However, recent evidence suggest that dopamine and cocaine binding sites on the DAT are distinct (Kityama et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 7782-7785).
Partial agonists and/or antagonists at the cocaine site on the dopamine transporter protein may show efficacy in treating cocaine addiction. Importantly, several compounds which bind to the cocaine binding site have been shown to block the effects of cocaine in vivo. For example, GBR 12909 has been shown to attenuate cocaine-induced activation of mesolimbic dopamine neurons in rat (Baumann et al., J. Pharm. Exp. Therap., 1994, 271, 1216-1222). Compounds which bind to the cocaine site but do not inhibit dopamine uptake (i.e. a cocaine antagonist) may have utility in the treatment of cocaine addiction (Carroll, FI et al., Pharmaceutical News, 1994, 1, 11-17).
There are currently no medications which effectively treat cocaine addiction. Accordingly, a need exists for compounds having an affinity for the cocaine site on a dopamine transporter protein (DAT), without inhibiting dopamine uptake, to aid in the treatment of cocaine addiction.
A further need exists for compounds which inhibit dopamine uptake to aid in the treatment of neurological disorders characterized by abnormal dopaminergic neurotransmission, notably Parkinson's disease, depression, and attention deficit disorder (ADD).
The applicant has discovered new compounds that are useful for the above described treatments, as well as new methods of using known compounds that are related in structure to the new compounds.